Uteroplacental insufficiency retards fetal growth and limits the supply of critical substrates to the fetus resulting in an altered redox state and oxidative stress. This abnormal metabolic intrauterine milieu affects fetal development by permanently modifying gene expression and function of susceptible cells, such as the beta-cell. Pdx-1 is a pancreatic homeobox transcription factor that regulates critical aspects of beta-cell function and development. As early as 24 hours after the onset of growth retardation, Pdx-1 mRNA levels are reduced by more than 50%. We have determined that decreased Pdx-1 expression is due to a reduction in Pdx-1 transcription. Suppression of Pdx-1 expression persists after birth and progressively declines in the IUGR animal, suggesting that an epigenetic mechanism may be responsible (via DNA methylation and or histone modifications) for decreased transcription of Pdx-1. A CpG island exists within the proximal promoter and first exon of Pdx-1, a highly conserved region that contains a critical USF (a helix-loop-helix/leucine zipper transcription factor) binding site that is obligate for Pdx-1 transcription. We hypothesize that: (1) oxidative stress in the IUGR fetus impairs USF binding which induces histone modifications, followed by DNA methylation thereby locking in suppression of Pdx-1 transcription. As the animal ages, chromatin remodeling spreads to the enhancer regions of the Pdx-1 gene causing further transcriptional repression. (2) IUGR induced epigenetic modifications are tissue specific and gene specific and occur only in organs that are sensitive to oxidative stress, such as pancreas. We will test this hypothesis by determining the mechanisms by which epigenetic modifications suppress Pdx-1 expression, whether oxidative stress in normal islets induces epigenetic modifications of key regulatory regions and leads to decreased transcription of Pdx-1, and whether IUGR induces widespread epigenetic modifications, and determine whether these epigenetic modifications are tissue and gene specific.